WO2002056895A2 - Polymeres d'ionene et leur utilisation dans le traitement de la mucosite - Google Patents

Polymeres d'ionene et leur utilisation dans le traitement de la mucosite Download PDF

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WO2002056895A2
WO2002056895A2 PCT/US2002/001118 US0201118W WO02056895A2 WO 2002056895 A2 WO2002056895 A2 WO 2002056895A2 US 0201118 W US0201118 W US 0201118W WO 02056895 A2 WO02056895 A2 WO 02056895A2
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substituted
unsubstituted
group
mucositis
formula
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WO2002056895A3 (fr
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Richard Fitzpatrick
Philip J. Goddard
Robert H. Barker, Jr.
Keith K. Shackett
Jeffrey D. Klinger
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Genzyme Corporation
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
    • C08G73/0622—Polycondensates containing six-membered rings, not condensed with other rings, with nitrogen atoms as the only ring hetero atoms
    • C08G73/0627—Polycondensates containing six-membered rings, not condensed with other rings, with nitrogen atoms as the only ring hetero atoms with only one nitrogen atom in the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G61/12—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/0206—Polyalkylene(poly)amines
    • C08G73/0213—Preparatory process
    • C08G73/0226—Quaternisation of polyalkylene(poly)amines

Definitions

  • Oral mucositis is a common, painful, dose-limiting toxicity of drug and radiation therapy for cancer.
  • the disorder is characterized by breakdown of the oral mucosa, which results in the formation of ulcerative lesions.
  • ulcerations that accompany mucositis are frequent portals of entry for indigenous oral bacteria leading to sepsis or bacteremia.
  • Mucositis occurs to some degree in more than one third of all patients receiving anti-neoplastic drug therapy, and there are about one million occurrences of oral mucositis annually in the United States. The frequency and severity are significantly greater among patients who are treated with induction therapy for leukemia or with many of the conditioning regimens for bone marrow transplant.
  • Chlorhexidine mouthwash is extensively used in oral mucositis treatment and prevention, however, its efficacy is decreased in saliva and it is relatively ineffective against the Gram negative bacteria that tend to colonize the oral cavity. Thus, there is a need for new treatments that inhibit, prevent, reduce the severity, and/or promote the healing of mucositis.
  • This invention relates to the use of polyionenes are effective in treating or preventing oral mucositis in hamsters.
  • the polyionene poly(4,4'- trimethylenebis(l-methylpiperidinium)-alt-octane (X) was effective in significantly reducing the severity of oral mucositis at a concentration as low as 1.0 mg/mL. This contrasts with chlorhexidine, which is commonly used to treat oral mucositis but was unsuccessful in treating the hamster model at a concentration of 0.5% (v/v).
  • the method of treating mucositis comprises administering to the mammal an effective amount of an ionene polymer.
  • the ionene polymer comprises a repeat unit represented by Structural
  • the polymer may be comprised of identical or non-identical repeat units so as to form either a homopolymer or a copolymer.
  • Ri is a substituted or unsubstituted hydrocarbyl group.
  • Ri is a substituted or unsubstituted arylene or lower alkylene group.
  • Each Q is represented by Structural Formula (II), (ffl), (TV), (V), or (VI):
  • Cyi and Cy 2 are each independently a quaternary nitrogen-containing monocyclic heteroaromatic ring or non-aromatic heterocyclic ring.
  • A is a covalent bond, or a substituted or unsubstituted lower alkylene group.
  • R and R 3 are independently a substituted or unsubstituted aliphatic or aromatic group.
  • R 2 and R 3 are each independently an alkyl group or a hydroxyalkyl group.
  • Each X “ is a physiologically acceptable anion.
  • the values x and y are integers, where x is an integer from 0-4 or from 1-4 and y is an integer from 1-5 or from 2-5.
  • the ionene polymers of the present invention have been found to be effective in the treatment of oral mucositis.
  • the ionene polymers of this invention additionally have been found to be non-irritating and low in toxicity to warmblooded animals.
  • the present invention provides a method of using ionene polymers in pharmaceutical compositions for the treatment of mucositis.
  • ionene polymers or “polyionenes,” as used in the present invention, are cationic polymers or copolymers with quatemized nitrogen or phosphorus located in the main polymeric chain or backbone of the polymer, providing a positive charge.
  • Polyionenes can also be polyguanidines or copolymers thereof, where the cationic nitrogen atom is an imide nitrogen directly bonded to the polymer backbone.
  • the molecular weight of the ionene polymers of the present invention is generally not limiting, but each polymer typically comprises from 50 to about 500 repeat units.
  • Mucositis is defined herein as inflammation and/or ulceration of a mucous membrane.
  • the disclosed method can be used to treat mucositis in the stomach, intestines, and the like; however, it is particularly effective when used to treat oral mucositis.
  • Oral mucositis is characterized by inflammation of a mucous membrane of the oral cavity or lips and is typically accompanied by redness, swelling, and/or ulcerations of the mouth. Included in this description is oral mucositis that is a side- effect of anti-cancer therapies such as chemotherapy and radiotherapy, and oral mucositis that is a side effect of bone marrow transplantation or stem cell transplant or ablation.
  • Mucositis also includes mucositis that develops spontaneously in a healthy patient not receiving anti-cancer therapy, as in the case of a canker sore or mouth ulcer.
  • Treatment includes both prophylactic and therapeutic uses of the ionene polymers.
  • Desired prophylactic effects include prevention of and inhibition of mucositis, reduction in severity of mucositis, reduction in size of mucositis lesions compared with, for example, what is normally experienced by a mammal undergoing cancer therapy, and reduction in likelihood of developing mucositis.
  • Desired therapeutic effects include amelioration of the discomfort associated with the oral mucositis, and/or increased rate of healing of mucositis lesions compared with, for example, what is normally experienced by a mammal undergoing cancer therapy.
  • the invention provides, in one aspect, a method of treating mucositis or oral mucositis comprising administering an effective amount of an ionene polymer.
  • Q is represented by Structural Formula (TV) and Cyi is a piperidinium ring having a quaternary nitrogen additionally substituted with a hydrogen or a substituted or unsubstituted lower alkyl group. More preferably, the quaternary nitrogen is additionally substituted with a lower alkyl or hydroxy substituted lower alkyl group.
  • An example of a "piperidinium" ionene repeat unit is represented in Structural Formula (VH):
  • Q is represented by Structural Formula (V) and Cyi and Cy 2 are each piperidinium rings having a quaternary nitrogen additionally substituted independently with a hydrogen or a substituted or unsubstituted lower alkyl group and A is as defined above. More preferably, the quaternary nitrogen is additionally substituted with a lower alkyl or hydroxy substituted lower alkyl group.
  • An example of a "piperidinium" ionene repeat unit of this type is represented in Structural Formula (LX):
  • R 5 and Rg are each independently hydrogen or a substituted or unsubstituted lower alkyl group.
  • R5 and R 6 are each independently an alkyl group or a hydroxyalkyl group, and A is an unsubstituted straight chained lower alkylene group.
  • A is an unsubstituted straight chained lower alkylene group and Ri is a substituted or unsubstituted straight chained lower alkylene or polyalkylene group optionally substituted with one or more hydroxyl groups, preferably an unsubstituted polyalkylene glycol or -CH 2 CHOH(CH 2 ) n CHOHCH 2 - where n is an integer ranging from 0 to 8.
  • Specific examples of "piperidinium" ionene repeat units are represented by the Structural Formulas (X), (XI), (XII), (Xffl), (XIV), and (XV):
  • Q is represented by Structural Formula (V) and Cyi and Cy 2 are each pyridinium groups and A is as defined above.
  • a "pyridinium" ionene polymer of this type the polymer is characterized by repeat units represented by Structural Formula (XVI):
  • a and Ri are as defined above.
  • A is an unsubstituted straight chained lower alkylene group.
  • Ri is a substituted or unsubstituted straight chained lower alkylene or polyalkylene glycol group optionally substituted with one or more hydroxyl groups, preferably an unsubstituted polyalkylene or -CH 2 CHOH(CH 2 ) n CHOHCH 2 - where n is an integer ranging from 0 to 8.
  • An example of a repeat unit with these components is represented by Structural Formula (XVH):
  • pyridinium ionene polymers are represented by Structural Formulas (XVIH), (XIX), (XX), (XXI), (XXII), (XXIII), and (XXIV):
  • Another polyionene suitable for use in the present invention comprises a repeat unit where Q is represented by Structural Formula (II).
  • Q is represented by Structural Formula (U)
  • Ri is preferably a substituted or unsubstituted phenylene, lower alkylene, polyalkylene glycol group, or
  • Ri is a substituted or substituted straight chained lower alkylene group or polyalkylene glycol optionally substituted with one or more hydroxyl groups.
  • Yet another polyionene suitable for use in the present invention comprises a repeat unit where Q is represented by Structural Formula (HT).
  • Q is represented by Structural Formula (IH)
  • Ri is preferably a substituted or unsubstituted arylene, lower alkylene, polalkylene glycol group, or -CH 2 CHOH(CH 2 ) n CHOHCH 2 -, where n is integer ranging from 0 to 8, and .
  • R 2 and R 3 are as defined above. Even more preferably, R t is a substituted or substituted straight chained lower alkylene group or polyalkylene glycol optionally substituted with one or more hydroxyl groups.
  • R t is a substituted or substituted straight chained lower alkylene group or polyalkylene glycol optionally substituted with one or more hydroxyl groups.
  • a specific example is represented by Structural Formula (XXV):
  • Q is represented by Structural Formula (VI).
  • Ri is an unsubstituted lower alkylene or lower alkylene glycol group and x is 1 and y is 2; x is 1 and y is 3; x is 1 and y is 4; or x is 1 and y is 5.
  • Specific examples of guanidine ionene polymers and copolymers comprise repeat units of formulas (XXVI), (XXVII), (XXVffl), and (XXLX):
  • ionene polymers suitable for use in the disclosed method include homopolymers and copolymers.
  • the variables in each repeat unit of a copolymer of the present invention are independently selected.
  • the alkylene group represented by A in one repeat unit can differ from the alkylene group represented by A in other repeat units.
  • Q is identical in all repeat units and Ri varies; Ri is identical in all repeat units and Q varies; or Q and Ri each vary among repeat units.
  • Q, Ri, and A are identical in all repeat units.
  • ionene copolymer where Q varies within the polymer
  • Q is represented by Structural Formula (H) and Structural Formula (HI).
  • This copolymer is comprised of repeat units represented by Structural Formulas (XXXa) and (XXXb):
  • R ls R 2 , R 3 and X are as defined above, and are chosen independently for each repeat unit. That is, R ls R , R 3 , and X are not necessarily the same throughout the copolymer.
  • the repeat units of Structural Formulae (XXXa) and (XXXb) alternate to form a repeat unit represented by Structural Formula (XXXI):
  • Rio is a substituted or unsubstituted lower alkylene group having 1 to about 24 carbon atoms, preferably having about 4 to about 12 carbon atoms.
  • Each X " separately or taken together with other X " s, is a physiologically acceptable anion.
  • ionene copolymer where Q varies within the copolymer, Q alternates between repeat units represented by Structural Formulae ( ⁇ )-(V), (X)-(XV), or (XV ⁇ )-(XX ⁇ ) and a repeat unit represented by Structural Formula (VT).
  • Structural Formula (XXXII) One copolymer of this type is represented by Structural Formula (XXXII):
  • An "aliphatic group” is non-aromatic, consists solely of carbon and hydrogen and may optionally contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched, or cyclic and typically contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • Aliphatic groups are preferably lower alkyl groups or lower alkylene groups, which include Cl-24 (preferably C1-C12) straight chained or branched saturated hydrocarbons.
  • An alkyl group is a saturated hydrocarbon in a molecule that is bonded to one other group in the molecule through a single covalent bond from one of its carbon atoms.
  • Examples of lower alkyl groups include methyl, ethyl, ra-propyl, iso -propyl, n-butyl, sec-butyl and tert-butyl.
  • An oxyalkyl group is an alkyl group where an oxygen atom connects the alkyl group and one other group.
  • alkylene group is a saturated hydrocarbon in a molecule that is bonded to two other groups in the molecule through single covalent bonds from two of its carbon atoms.
  • Examples of lower alkylene groups include methylene, ethylene, propylene, ⁇ -propylene (-CH(CH 2 )CH 2 -), butylene, sec-butylene (-CH(CH 3 )CH 2 CH 2 -), and tert-butylene
  • Aromatic groups include carbocyclic aromatic groups such as phenyl, 1- naphthyl, 2-naphthyl, 1-anthracyl and 2-anthacyl, and heterocyclic aromatic groups such as N-imidazolyl, 2-imidazole, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazole, 4-thiazole, 5-thiazole, 2- oxazolyl, 4-oxazolyl and 5-oxazolyl.
  • Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings.
  • Examples include 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazole, 2- benzooxazole, 2-benzimidazole, 2-quinolinyl, 3-quinolinyl, 1-isoquinolinyl, 3- quinolinyl, 1-isoindolyl and 3-isoindolyl.
  • Phenyl is a preferred aromatic group.
  • Arylene is an aromatic ring(s) moiety in a molecule that is bonded to two other groups in the molecule through single covalent bonds from two of its ring atoms. Examples include phenylene -[-(C6H4)-], thienylene [-(C4H2S)-] and furanylene [-(C4H2O)-].
  • a polyalkylene glycol is an alkylene group, which includes one or more ether linkages, where the chain includes a total of about 1 to about 12 carbon and oxygen atoms, and is optionally substituted with one or more hydroxyl groups.
  • the polyalkylene glycol is polyethylene glycol or polypropylene glycol.
  • a “hydrocarbyl group” is an alkylene or arylene group, i.e., -(CH2) X - or -(CH 2 ) X C 6 H 4 (CH 2 ) X - where x is a positive integer (e.g., from 1 to about 30), preferably between 6 and about 30, more preferably between about 6 and about 15.
  • the carbon chain of the hydrocarbyl group maybe optionally interrupted with any combination of ether (-0-), thioether (-S-), amine [-N(R a )-] or ammonium [-N + (R a R D )-] linkages.
  • R a and R° are independently -H, alkyl, substituted alkyl, phenyl, or substituted phenyl.
  • R a and R° can be the same or different, but are preferably the same.
  • hydrocarbyl groups include butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, dodecylene, 4-oxaoctylene, 4-azaoctylene, 4-thiaoctylene, 3,6-dioxaoctylene, 3,6-diazaoctylene, and 4,9-dioxadodecane.
  • Suitable substituents on an aliphatic, aromatic or benzyl group are those that do not substantially decrease the mucositis-treating properties of the molecule (e.g., increase the ED50 by more than a factor often).
  • Each R is independently -H, an aliphatic group, a substituted aliphatic group, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group, and preferably -H, a lower alkyl group, a benzylic group or a phenyl group.
  • a substituted benzylic group or aromatic group can also have an aliphatic or substituted aliphatic group as a substituent.
  • a substituted aliphatic group can also have a benzyl, substituted benzyl, aromatic or substituted aromatic group as a substituent.
  • a substituted aliphatic, substituted aromatic or substituted benzyl group can have more than one substituent.
  • a preferred substituent on an aliphatic group is -OH.
  • the anions represented by X " in the polymer can be the same or different.
  • Each X" in a repeat unit can separately be a monovalent anion, i.e., an anion having a negative charge of one.
  • two or more X"s in the same repeat unit or in different repeat units, taken together, can represent an anion having a negative charge of two, three or more.
  • a polymer can comprise anions of different charges.
  • Suitable counteranions include sulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, proprionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, fumarate, maleate, benzoate, sulfonate, phenylacetate, citrate, lactate, glycolate, tartrate and the like. Bromide and chloride are preferred.
  • One anion can be exchanged for another by passing a solution containing the desired counter anion over the polymer.
  • physiologically acceptable salts of the polymers having repeat units represented by Formulas VI and XXVI-XXLX can be formed by reacting the polymer with a suitable acid. Examples include the corresponding acid of the salts listed in the previous paragraph.
  • the hydrochloride and hydrobromide salts are preferred.
  • the polymer can be administered alone or in a pharmaceutical composition comprising the polymer, a pharmaceutically acceptable carrier, and optionally; one or more additional drugs, e.g., antibiotics or antimicrobials.
  • additional drugs e.g., antibiotics or antimicrobials.
  • antibiotics or antimicrobials examples include streptomycin, rifamycin, amphotericin B, griseofulvin, penicillin, cephalothin, cefazolin, chloramphenicol, fluconazole, clindamycin, erythromycin, bacitracin, vancomycin, ciprofloxiacin, tertracycline, and fusidic acid.
  • the polymers can be administered, for example, topically, orally, intranasally, by aerosol or rectally.
  • the form in which the polymer is administered depends in part on the route by which it is administered.
  • the polymer is preferably administered orally as a gargle, an ointment, a swab, a gel, and the like.
  • Suitable carriers and diluents for an ionene polymer will be immediately apparent to persons skilled in the art.
  • These carrier and diluent materials include, for example, gelatin, lactose, starch, magnesium stearate, preservatives (stabilizers), sugars, emulsifying agents, salts and buffers.
  • examples of pharmaceutically acceptable carriers include, for example, commercially available inert gels, or liquids supplemented with albumin, methyl cellulose, or a collagen matrix.
  • an effective amount of an ionene polymer to be administered will be determined on an individual basis, and will be determined at least in part, by consideration of the individual's size, the severity of symptoms to be treated and the result sought. As used herein, an effective amount refers to an appropriate amount of ionene polymer, which results in a desired therapeutic or prophylactic effect with respect to mucositis, as defined above.
  • Typical dosages for applied and/or ingested ionene polymers range from between about 0.05 ⁇ g/kg body weight to about 500 mg/kg body weight, more typically between about 0.1 ⁇ g/kg body weight to about 100 mg/kg body weight and even more typically between about 0.5 ⁇ g/kg body weight and about 10 mg/kg body weight.
  • the method of the claimed invention is particularly useful in the treatment of oral mucositis resulting from anti-cancer therapy, such as radiation therapy or chemotherapy, including induction therapy in leukemia patients.
  • anti-cancer therapy such as radiation therapy or chemotherapy
  • the treatment can be particularly beneficial for patients undergoing treatment for tumors of the head and neck, such as radiation patients.
  • treatment with an ionene polymer is initiated before the onset of the chemotherapy, during chemotherapy, after chemotherapy is complete but before symptoms appear or any combination of the above.
  • treatment with the ionene polymer is initiated before the onset of radiation therapy, during radiation exposure, after radiation exposure has been terminated (preferably no sooner than about one hour, more preferably five hours after termination) but before symptoms appear or any combination of the above.
  • the ionene polymer is administered after symptoms of mucositis (e.g., mouth ulcers) have appeared.
  • Ionene polymers of the present invention can be prepared by a reacting a divalent electrophile such as an ⁇ , ⁇ -dihalogenated alkane or a corresponding diepoxide with a divalent nucleophile such as 4,4'-trimethylenedipiperidine or N,N,N',N'-tetramethyl-l,3-propanediamine.
  • a divalent electrophile such as an ⁇ , ⁇ -dihalogenated alkane or a corresponding diepoxide
  • a divalent nucleophile such as 4,4'-trimethylenedipiperidine or N,N,N',N'-tetramethyl-l,3-propanediamine.
  • the divalent nucleophile is an ⁇ , ⁇ -diaminoalkane or an ⁇ , ⁇ -aminoguanidine and the divalent electrophile typically is an ⁇ , ⁇ -biscyanoguanidine.
  • Polymerizing with one divalent electrophile and one divalent nucleophile results in a homopolymer.
  • Polymerizing with two or more divalent electrophiles and/or divalent nucleophiles results in a copolymer.
  • Such homopolymers and copolymers are encompassed within the present invention.
  • Polyionene polymers are typically "capped" at the termini with a partially reacted divalent electrophile or nucleophile or a monovalent electrophile or nucleophile. For example, when polymerizing 4,4'-trimethylenepyridine and 1,6- dibromohexane (or the corresponding epoxide), the resulting polymer is capped at either end with one of the following groups:
  • the capping group can be reacted further, for example, by hydrolyzing the epoxide or reacting the halide or epoxide with a nucleophile.
  • An example of a capping group for polyguanidine polymers or copolymers is represented by Structural Formula (XXXIV):
  • Ionene polymers of the invention may also be cross-linked with primary, secondary or other polyfunctional amine using means known in the art.
  • Ionene polymers can be cross-linked by polymerizing in the presence of a multivalent nucleophile (i.e., a compound with three or more nucleophilic groups such as a triamine or tetraamine) or a multivalent electrophile (i.e., a compound with three or more nucleophilic groups such as a trihalide or tetrahalide).
  • a multivalent nucleophile i.e., a compound with three or more nucleophilic groups such as a triamine or tetraamine
  • a multivalent electrophile i.e., a compound with three or more nucleophilic groups such as a trihalide or tetrahalide
  • 1,12-dodecanediamine (3.99 mmoles, 0.848 ml) were added to a 40 ml vial with a septa-cap followed by 2 equivalents of concentrated HC1. The mixture was heated to 135-145° C in a shaker overnight. The resulting clear yellow, brittle solid was dissolved in water and purified by centrifugation through a 3K Macrosep filtration membrane.
  • 4,4'-Trimethylenebis(l-methylpiperidine)-alt-l,8-Dibromooctane was prepared by dissolving 4,4'-Trimethylenebis(l-methylpiperidine) (39.9 ml) in 30 ml of DMF in a 250 ml Erlemneyer flask. 1,8-Dibromooctane (27.63 ml) was also added to the flask. The reaction was purged with nitrogen, covered with a septum, and stirred with a magnetic stir plate. The initial solution was clear. After approximately 20 minutes of stirring the reaction exothermed and solidified. A light yellow solid polymer formed and was left to further polymerize for a week. The polymer was dissolved in ⁇ 300 ml of deionized water and dialyzed (3500 molecular weight cut-off) in water 3x and lx in water/MeOH 70%/30%.
  • N,N,N',N'-Tetramethyl- 1 ,3-propanediamine-alt- 1 ,6-Dibromohexane was prepared by dissolving N,N,N',N'-Tetramethyl-1 ,3-propanediamine (31.9 ml) in 40 ml of DMF in a 250 Erlenmeyer flask. 1,6-Dibromohexane (29.3 ml) was added to the flask. The reaction was purged with nitrogen, covered with a septum, and stirred with a magnetic stir plate. The initial solution was clear. A very quick reaction that exothermed and solidified occurred. An off white solid polymer formed and was left to further polymerize for a week. The polymer was dissolved in approximately 300 ml of deionized water and dialyzed (3500 MW) in water 3x and lx in water/MeOH 70%/30%.
  • Hexamethylenebiscyanoguanidine (3.99 mmoles, 1.00 g) and 1,9- diaminononane (3.99 mmoles, 0.623 g) were added to a 40 ml vial with a septa-cap followed by 2 equivalents of concentrated HC1. The mixture was heated to 135-145° C in a shaker overnight. The solid was dissolved in water and purified by centrifugation through a 3K Macrosep filtration membrane.
  • 1,10-dibromodecane (1.73 mmoles, 1.04 g) were dissolved in DMF (1 ml) and shaken for 1 week. The resulting viscous liquid was diluted with water and purified by centrifugation through a 3K Macrosep.
  • EXAMPLE 15 Preparation of poly(l,4-bis(diphenylphosphonium)butane-alt-butane) (XXV). l,4-Bis(diphenylphosphino)butane (2.31 mmoles, 0.986 g) and 1,4- dibromobutane (2.31 mmoles, 0.276 g) were dissolved in DMF (1.333 ml) and shaken for 1 week. The resulting viscous liquid was diluted with water and purified by centrifugation through a 3K Macrosep.
  • Hydroxyl-containing polymer (XVII) was cross-linked with 6 mole % 1,6-diisocyanatohexane in DMF to produce a gel. The gel was washed with 70% methanol-water and lyophilized.
  • Trimethylenedipyridine (lOOg) was placed in a roundbottom flask. To the flask was added 1,2,7,8-diepoxyoctane (71.72g). The reaction was stirred under nitrogen at room temperature for 20 min. until nearly all the trimethylenedipyridine was dissolved. At this time, acetic acid (121g) was slowly added dropwise over a 24hr period. The reaction was stirred at room temperature for an additional four days. The resulting material was dark blue and highly viscous. The solid was dissolved in water and purified by tangential flow with a IK MWCO membrane.
  • Oral mucositis is a frequent sequel to chemotherapeutic treatment for a number of cancers, as well as of irradiation for head and neck tumors. While the precise causes of mucositis remain unknown, oral microflora are thought to be involved in both the induction and exacerbation of disease.
  • the efficacy of polyionene polymers in treating oral mucositis was assayed according to a hamster model disclosed in Sonis et al, Oral Oncology 36:313 (2000), the entire teachings of which are incorporated herein by reference.
  • the left buccal pouch was everted, fixed and isolated using a lead shield. All animals were dosed with test material three times per day. A needleless tuberculin syringe containing 0.5 ml of the test compound was inserted into the left cheek pouch and the drug deposited into the pouch. Dosing began on Day 0 and continued until Day 19.
  • mice treated with polyionene compounds experienced a significant reduction in the percent time they experienced ulcerative mucositis.
  • animals treated with (X) at 1 mg/ml had a 46% reduction in ulcerative mucositis when compared to the control group.

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Abstract

L'invention concerne un procédé d'utilisation de polymères d'ionène servant à traiter la mucosite et la mucosite orale affectant des mammifères. Ce procédé consiste à administrer à un mammifère une quantité efficace d'un d'ionène afin de traiter la mucosite thérapeutiquement et de manière prophylactique.
PCT/US2002/001118 2001-01-18 2002-01-17 Polymeres d'ionene et leur utilisation dans le traitement de la mucosite WO2002056895A2 (fr)

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WO2004046223A2 (fr) * 2002-11-19 2004-06-03 Genzyme Corporation Polymeres de polyionene a liaisons hydrolysables
WO2004046109A3 (fr) * 2002-11-19 2004-07-15 Genzyme Corp Oligomeres and polymeres d'ionene
WO2004046223A3 (fr) * 2002-11-19 2004-11-18 Genzyme Corp Polymeres de polyionene a liaisons hydrolysables
JP2017530159A (ja) * 2014-10-02 2017-10-12 サイトソーベンツ・コーポレーション 放射線で誘発された粘膜炎、食道炎、小腸炎、大腸炎、及び胃腸管急性放射線症候群を予防又は治療するための胃腸管投与多孔質消化管吸着剤ポリマーの使用
EP3200805A4 (fr) * 2014-10-02 2018-07-11 Cytosorbents Corporation Utilisation de polymères poreux sorbants entériques administrés par voie gastrointestinale pour prévenir ou traiter la mucosite, l' sophagite, l'entérite, la colite, et le syndrome gastro-intestinal aigu d'irradiation induits par l'irradiation
US10314859B2 (en) 2014-10-02 2019-06-11 Cytosorbents Corporation Use of gastrointestinally administered porous enteron sorbent polymers to prevent or treat radiation induced mucositis, esophagitis, enteritis, colitis, and gastrointestinal acute radiation syndrome
JP2020172528A (ja) * 2014-10-02 2020-10-22 サイトソーベンツ・コーポレーション 放射線で誘発された粘膜炎、食道炎、小腸炎、大腸炎、及び胃腸管急性放射線症候群を予防又は治療するための胃腸管投与多孔質消化管吸着剤ポリマーの使用

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WO2002056895A3 (fr) 2004-02-19
US6955806B2 (en) 2005-10-18
EP1372675A2 (fr) 2004-01-02
WO2002080939A3 (fr) 2003-10-09
WO2002080939A2 (fr) 2002-10-17
US20030031644A1 (en) 2003-02-13
NZ526821A (en) 2005-02-25
US20070025954A1 (en) 2007-02-01
US20030021761A1 (en) 2003-01-30
BR0206734A (pt) 2004-03-02

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